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Partitioning of cancer therapeutics in nuclear condensates.
Klein, Isaac A; Boija, Ann; Afeyan, Lena K; Hawken, Susana Wilson; Fan, Mengyang; Dall'Agnese, Alessandra; Oksuz, Ozgur; Henninger, Jonathan E; Shrinivas, Krishna; Sabari, Benjamin R; Sagi, Ido; Clark, Victoria E; Platt, Jesse M; Kar, Mrityunjoy; McCall, Patrick M; Zamudio, Alicia V; Manteiga, John C; Coffey, Eliot L; Li, Charles H; Hannett, Nancy M; Guo, Yang Eric; Decker, Tim-Michael; Lee, Tong Ihn; Zhang, Tinghu; Weng, Jing-Ke; Taatjes, Dylan J; Chakraborty, Arup; Sharp, Phillip A; Chang, Young Tae; Hyman, Anthony A; Gray, Nathanael S; Young, Richard A.
Affiliation
  • Klein IA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Boija A; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Afeyan LK; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Hawken SW; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Fan M; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Dall'Agnese A; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Oksuz O; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Henninger JE; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Shrinivas K; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Sabari BR; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Sagi I; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Clark VE; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Platt JM; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Kar M; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • McCall PM; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Zamudio AV; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Manteiga JC; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Coffey EL; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Li CH; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Hannett NM; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Guo YE; Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.
  • Decker TM; Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.
  • Lee TI; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
  • Zhang T; Center for Systems Biology Dresden, 01307 Dresden, Germany.
  • Weng JK; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Taatjes DJ; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Chakraborty A; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Sharp PA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Chang YT; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Hyman AA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Gray NS; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Young RA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Science ; 368(6497): 1386-1392, 2020 06 19.
Article in En | MEDLINE | ID: mdl-32554597
ABSTRACT
The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cell Nucleus / Drug Resistance, Neoplasm / Neoplasms / Antineoplastic Agents Limits: Humans Language: En Journal: Science Year: 2020 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cell Nucleus / Drug Resistance, Neoplasm / Neoplasms / Antineoplastic Agents Limits: Humans Language: En Journal: Science Year: 2020 Document type: Article Affiliation country: Estados Unidos